L-serine (Ser)

L-serine is a naturally occurring, non-essential amino acid that serves as a fundamental building block for proteins and a central hub in human metabolism. It is a vital precursor for the synthesis of essential compounds such as sphingolipids, phosphatidylserine, and the neurotransmitters glycine and D-serine [7, 11]. In the central nervous system, L-serine is primarily synthesized by astrocytes and is necessary for neuronal development, myelin maintenance, and synaptic plasticity through its conversion to D-serine, a co-agonist of the N-methyl-D-aspartate (NMDA) receptor [9, 13]. Clinically, L-serine is being investigated as a neuroprotective agent for several conditions, including Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, and Hereditary Sensory and Autonomic Neuropathy Type 1 (HSAN1) [1, 3, 20]. In ALS, high-dose L-serine is hypothesized to prevent the misincorporation of toxic amino acid analogs into proteins, while in HSAN1, it effectively reduces the accumulation of neurotoxic deoxysphingolipids [3, 5, 12]. Although widely available as a dietary supplement and generally regarded as safe (GRAS), its therapeutic use involves significantly higher doses that require clinical monitoring for gastrointestinal side effects [1, 17, 18].

Other names

(S)-2-amino-3-hydroxypropanoic acidSerineL-2-amino-3-hydroxypropionic acid(S)-serine2-amino-3-hydroxypropanoic acid

L-serine acts as a metabolic precursor for the synthesis of D-serine (a critical co-agonist of the NMDA receptor) and glycine (an inhibitory neurotransmitter) [6, 9]. In neurodegenerative contexts like ALS, it is proposed to provide neuroprotection by competitively inhibiting the misincorporation of the neurotoxin BMAA into proteins, thereby preventing protein misfolding [5, 20]. In Hereditary Sensory and Autonomic Neuropathy Type 1 (HSAN1), L-serine supplementation shifts the substrate preference of the enzyme serine palmitoyltransferase (SPT) away from alanine and glycine, which reduces the production of neurotoxic 1-deoxysphingolipids [3, 7]. It also functions as a direct agonist at glycine receptors and has been shown to upregulate PPAR-gamma expression to mitigate neuroinflammation [3, 10].